21-44288472-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000383.4(AIRE):c.652+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,561,414 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 24 hom., cov: 33)

Exomes 𝑓: 0.016 ( 238 hom. )

Consequence

AIRE
NM_000383.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -2.97

Publications

3 publications found

Variant links:

Genes affected

AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]

AIRE Gene-Disease associations (from GenCC):

autoimmune polyendocrine syndrome type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Myriad Women’s Health, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial isolated hypoparathyroidism due to impaired PTH secretion
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AIRE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 21-44288472-C-T is Benign according to our data. Variant chr21-44288472-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35667.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1872/152272) while in subpopulation NFE AF = 0.0199 (1350/68006). AF 95% confidence interval is 0.019. There are 24 homozygotes in GnomAd4. There are 853 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.652+14C>T		intron_variant	Intron 5 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
AIRE	ENST00000291582.6 link	c.652+14C>T	intron_variant	Intron 5 of 13	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000530812.5 link	n.1218C>T	non_coding_transcript_exon_variant	Exon 4 of 12	2
AIRE	ENST00000527919.5 link	n.1196+14C>T	intron_variant	Intron 4 of 13	2

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1875

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0199

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0131

AC:

3247

AN:

247102

AF XY:

0.0134

show subpopulations

Gnomad AFR exome

AF:

0.00313

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00298

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0160

AC:

22588

AN:

1409142

Hom.:

238

Cov.:

AF XY:

0.0159

AC XY:

11203

AN XY:

703036

show subpopulations

African (AFR)

AF:

0.00299

AC:

AN:

32414

American (AMR)

AF:

0.0108

AC:

481

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

561

AN:

25776

East Asian (EAS)

AF:

0.00

AC:

AN:

39384

South Asian (SAS)

AF:

0.00617

AC:

525

AN:

85158

European-Finnish (FIN)

AF:

0.00404

AC:

210

AN:

52030

Middle Eastern (MID)

AF:

0.0295

AC:

167

AN:

5656

European-Non Finnish (NFE)

AF:

0.0184

AC:

19643

AN:

1065494

Other (OTH)

AF:

0.0154

AC:

904

AN:

58676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1112

2224

3335

4447

5559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1872

AN:

152272

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

853

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00313

AC:

130

AN:

41556

American (AMR)

AF:

0.0126

AC:

193

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00436

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0199

AC:

1350

AN:

68006

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

198

298

397

496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0159

Hom.:

Bravo

AF:

0.0124

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AIRE: BS1, BS2 -

Mar 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173) -

Polyglandular autoimmune syndrome, type 1

Uncertain:1Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 15, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.91

(source)

DANN

Benign

0.71

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over